Aggressive cervical neuroblastoma with a rare paraneoplastic syndrome: A therapeutic dilemma.

Neuroblastoma is infrequently associated with paraneoplastic syndromes. Amongst the few, opsomyoclonus (Kinsbourne syndrome) is the most common neurological paraneoplastic syndrome and diarrhea secondary to increased secretion of vasoactive intestinal peptide (Kerner-Morrison syndrome), hormonal paraneoplastic syndrome. Hypothalamic dysfunction (HD) is a rare disorder and its manifestation as a paraneoplastic syndrome of neuroblastoma is uncommonly reported. We present an interesting case of an unrelenting cervical neuroblastoma associated with HD, which posed a therapeutic challenge.

INTRODUCTION

Neuroblastoma has been associated with neurological paraneoplastic syndromes such as opsomyoclonus. However, hypothalamic dysfunction (HD) is very rare in neuroblastoma.[1] The causes of HD in children are hypothalamic tumors, trauma or congenital malformations.[2] In the absence of these, it could be a manifestation of a paraneoplastic syndrome. Less than 15 cases of HD associated with neural crest tumors, mainly neuroblastoma has been described.[2345] Unlike opsomyoclonus, the outcome with HD is not favorable. We present a case of aggressive cervical neuroblastoma with HD, which posed a therapeutic challenge in prioritizing the initial therapy.

CASE REPORT

A 4-year-old girl presented with a history of painless swelling in the neck since the last 8 months for which she was receiving empirical anti-tubercular treatment. The parents also noticed change in behavior of the child since the preceding 2 months in the form of irritability, irrational demands, frequent burst of violence, alteration in sleep pattern with insomnia, and noisy breathing while asleep. Patient also developed voracious appetite and a weight gain of 12 kg in 3 months and polyuria.

On general physical examination, the patient's body weight was 25 kg (>97th percentile), height was 1.15 m (>97th percentile), and body mass index was 18.93 kg/m2 (>97th percentile). Her pubertal stage was appropriate for age (Tanner stage 1 for breast and pubic hair). The patient had a moon face and buffalo hump but lacked hyperpigmentation, striae, and acne or muscle weakness [Figure 1]. The blood pressure was 140/90 mmHg (>95th percentile for age), and the child was irritable, aggressive, noncooperative, and anxious. However, intelligence was appropriate to her age, and there was no motor or sensory deficit. The patient had Horner's syndrome on the ipsilateral side of the disease. The neck mass was 6 cm × 6 cm firm and relatively fixed. Biopsy of the mass revealed a poorly differentiated neuroblastoma, which was categorized as Shimada unfavorable histology. Molecular studies with polymerase chain reaction revealed nonamplification of MYCN gene. The 24-hour urinary vanillylmandelic acid was 43.9 mg/g (normal range <13 mg/g), and serum lactate dehydrogenase was 429 U/L (normal range 105-333 IU/L). Computerized tomography scan of the neck showed a large soft tissue mass with infiltration of sternocleidomastoid and paraspinal muscles and narrowing of the airway [Figure 2]. There was thrombosis of the internal jugular vein from the hyoid bone to the root of the neck and multiple enlarged cervical lymph nodes. Metaiodobenzylguanidine scan revealed increased tracer uptake in the cervical mass and no other scintigraphy evidence of metastasis anywhere in the body. Bone marrow aspiration and biopsy were negative for tumor infiltration. Whole body positron emission tomography (PET) scan revealed a hypermetabolic neck mass along with multiple cervical lymph nodes. Endocrine work-up revealed basal cortisol level of 14.3 μg/dl (normal range 5-25 μg/dl) and basal adrenocorticotropic hormone (ACTH) of 41.9 pg/L (normal range 10-60 pg/m). Three consecutive 24 h urinary free cortisol values were 420, 573, and 348 ug/dl (normal range: 58-403 μg/dl). Diurnal rhythm of cortisol axis was well preserved, and serum cortisol after overnight dexamethasone suppression test was 1.5 μg/dl (normal: <1.8 μg/dl). Thus, diagnosis of Cushing's syndrome was excluded. Thyroid function tests were also normal. Serum calcium, alkaline phosphatase, and phosphorus were 9.2 mg/dl, 119 U/I, and 3.5 mg/dl, respectively. Serum electrolytes were within normal range. Magnetic resonance imaging of the brain and cerebrospinal fluid examination was normal. The clinical features and the endocrine work-up suggested HD. However, the large cervical mass compromising the airway compelled initiating therapy for neuroblastoma, and further investigation of HD was deferred.

Figure 1

Clinical picture showing typical cushingoid features and right sided neck mass

Figure 2

Axial computed tomography scan image showing a large cervical mass encasing the internal carotid artery (arrow) and narrowing (arrow head) of the airway

Patient received four cycles of doxorubicin, cisplatin, and etoposide. The blood pressure was controlled on amlodipine 2.5 mg/day. Postchemotherapy PET scan suggested a marginal increase in the size of the mass with no significant change in metabolism with few new nodes in the right supraclavicular region. Excision of the cervical mass with level I-V lymph nodes and internal jugular vein was performed. Postoperative period was uneventful, however, all the behavioral abnormalities, hyperphagia, and sleep alteration persisted. The patient received postoperative radiotherapy and two more cycles of chemotherapy. At 3 months from completion of treatment, the patient developed isolated axillary lymph node relapse. Excision of the relapse and salvage chemotherapy was initiated. However, the patient developed a massive anterior mediastinal mass while on chemotherapy. In view of progressive disease, only symptomatic treatment was offered. The child expired 2 months later at home.

DISCUSSION

The association of neuroblastoma with neurological abnormalities other than opsomyoclonus is very rare. HD is a rare clinical entity with fewer than 15 cases associated with neural crest tumors.[2345] North et al. first reported idiopathic HD in a child, however; the presence of ganglioneuroma and diffuse infiltrate of lymphocytes and histiocytes in the hypothalamic region was confirmed only on autopsy.[3] Their group again reported a 3 and half-year-old boy with hyperphagia, obesity, polyuria, nocturnal respiratory irregularity, and markedly aggressive behavior.[4] The child died in 5 months of respiratory failure and on autopsy was found to have paravertebral ganglioneuroblastoma with positive regional lymph nodes, but there were no central nervous system metastases. There was only extensive lymphocytic infiltrate of hypothalamus, thalamus, midbrain, and medulla with associated neuronal loss and reactive astrocytosis. Similar to this presentation, our patient had behavioral changes, hyperphagia, and sleep disturbances, and investigation for central nervous system metastasis were negative. Sirvent et al., have reported two similar cases of abdominal neuroblastoma with behavioral abnormalities such as aggressive behavior, outbursts of euphoria and laughing, and irascibility, other symptoms such as hypersomnia, fluctuations in body temperature in one of the patients, while other had change in personality, psychomotor retardation, aggressive outbursts, impaired concentration, and hypersomnia.[2] These symptoms persisted even after adequate multimodal treatment of primary disease. In our patient, similarly the symptoms had persisted after treatment of the primary.

Many neurological paraneoplastic syndromes are associated with onconeural antibodies against neural antigens expressed by the tumor. However, they may occur without onconeural antibodies, and the antibodies can occur without a neurological syndrome.[6] The typical neuronal antibodies to Yo, Ri, Hu, or amphiphysin were absent in the previously reported patients with HD. Therefore, the treatment with immunosuppressive therapy is unclear. Notwithstanding, the absence of antibodies, Sirvent et al., offered immunosuppressive therapy to their patient, which was however, ineffective.[2]

Varying endocrine function ranging from normal to deficiencies could occur with idiopathic HD. One of the patients reported by Sirvent et al. had normal growth hormone; luteinizing hormone; follicle stimulating hormone; and thyroid function while the other had hypothalamic hypothyroidism, growth hormone deficiency, and marked hyperprolactinemia.[2] Our patient also had normal cortisol, ACTH, and thyroid function, although other pituitary hormones were not assessed in view of the overwhelming cervical disease compromising the airway. The patient had an early relapse after completion of therapy, which was followed by new site of relapse while on treatment for the relapse.

CONCLUSION

HD is a rare paraneoplastic syndrome of neuroblastoma. The treatment of the primary disease needs prioritization in presence of a compromised clinical scenario, which is emboldened by the fact that treatment of HD is variable, and symptoms due to HD are known to persist even after treatment of the primary. Neuroblastoma associated with HD is aggressive and has a poor outcome.

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Conflicts of interest

There are no conflicts of interest.